{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T06:56:11Z","timestamp":1769496971900,"version":"3.49.0"},"reference-count":20,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T00:00:00Z","timestamp":1698883200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T00:00:00Z","timestamp":1698883200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Eur J Med Res"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                <jats:title>Background<\/jats:title>\n                <jats:p>Primary biliary cholangitis (PBC) is a chronically progressive liver disease mediated by an autoimmune response. The aetiology and pathogenesis of PBC are not fully understood and may be related to immune disorders caused by genetic factors and their interaction with environmental factors. Immune checkpoints play an important role in preventing the occurrence of autoimmunity. However, the level of immune checkpoints in PBC has not been reported. Here, we aimed to identify the serum levels of soluble checkpoints in patients with PBC.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>Soluble checkpoint levels were evaluated using enzyme-linked immunosorbent assay in 60 patients with PBC and 20 healthy controls (HCs). The expression of immune checkpoints was compared in liver biopsy tissue samples using immunohistochemistry. Receiver operating characteristic (ROC) curves and area under the curve (AUCs) were used to determine the diagnostic performance of soluble checkpoints and laboratory indexes between patients with PBC and HCs and patients with mild and advanced PBC. A logistic regression was performed for advanced PBC.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>sCD134, sLAG-3, sPD-1, sPD-L1, and sTIM-3 levels were significantly increased in patients with PBC compared with those in healthy controls. Additionally, the levels of sCD134, sPD-1, sPD-L1, and sTIM-3 were positively associated with disease progression. Moreover, soluble checkpoints were correlated with immunoglobulin and liver functions. ROC analyses between patients with PBC and HCs showed that the AUCs of sOX40, sPD-1, and sPD-L1 were 0.967, 0.922, and 0.971, respectively. The optimal cut-off values of sOX40, sPD-1, and sPD-L1 for PBC diagnosis were 89.15, 213.4, and 68, respectively. ROC analyses between mild and advanced patients with PBC revealed that the AUCs of sOX40 and sTIM-3 were 0.767 and 0.765, respectively. The optimal cut-off values for predicting PBC stage\u2009\u2265\u2009III were 199.45 and 361.5, respectively. In univariate analysis, age, ALB, and sOX40 were associated with advanced PBC. Further, the expression of CD134 and TIM-3 was upregulated in the liver of patients with PBC.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our study results indicate that the serum titer of soluble checkpoints is increased in Chinese patients with PBC.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s40001-023-01419-6","type":"journal-article","created":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T03:02:19Z","timestamp":1698894139000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Soluble immune checkpoints are elevated in patients with primary biliary cholangitis"],"prefix":"10.1186","volume":"28","author":[{"given":"Xiuzhu","family":"Gao","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaomei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yazhe","family":"Guan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Liquan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanhang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junqi","family":"Niu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2023,11,2]]},"reference":[{"key":"1419_CR1","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.bpg.2018.05.008","volume":"34\u201335","author":"A Tanaka","year":"2018","unstructured":"Tanaka A, Leung PSC, Gershwin ME. Evolution of our understanding of PBC. Best Pract Res Clin Gastroenterol. 2018;34\u201335:3\u20139.","journal-title":"Best Pract Res Clin Gastroenterol"},{"key":"1419_CR2","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1007\/s00281-018-0715-8","volume":"41","author":"D Schwinge","year":"2019","unstructured":"Schwinge D, Schramm C. Sex-related factors in autoimmune liver diseases. Semin Immunopathol. 2019;41:165\u201375.","journal-title":"Semin Immunopathol"},{"key":"1419_CR3","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1038\/s41598-017-00906-1","volume":"7","author":"C Lu","year":"2017","unstructured":"Lu C, Hou X, Li M, Wang L, Zeng P, Jia H, et al. Detection of AMA-M2 in human saliva: Potentials in diagnosis and monitoring of primary biliary cholangitis. Sci Rep. 2017;7:796.","journal-title":"Sci Rep"},{"key":"1419_CR4","doi-asserted-by":"publisher","first-page":"102333","DOI":"10.1016\/j.jaut.2019.102333","volume":"104","author":"C Huang","year":"2019","unstructured":"Huang C, Zhu HX, Yao Y, Bian ZH, Zheng YJ, Li L, et al. Immune checkpoint molecules Possible future therapeutic implications in autoimmune diseases. J Autoimmun. 2019;104:102333.","journal-title":"J Autoimmun"},{"key":"1419_CR5","doi-asserted-by":"publisher","first-page":"21","DOI":"10.3390\/diseases8020021","volume":"8","author":"P Meister","year":"2020","unstructured":"Meister P, Steinke-Ramming C, Beste M, Lenzen H, Gerken G, Canbay A, et al. CTLA-4 expression plays a role in PSC and PBC progression. Diseases. 2020;8:21.","journal-title":"Diseases"},{"key":"1419_CR6","doi-asserted-by":"publisher","first-page":"5295164","DOI":"10.1155\/2017\/5295164","volume":"2017","author":"XC Yang","year":"2017","unstructured":"Yang XC, Fujino M, Cai SJ, Li SW, Liu C, Li XK. 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Each patient and healthy control signed an informed consent form. Our protocol was performed in accordance with the guidelines and regulations of the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"477"}}